Darstellung,Strukturen und EPR-Spektren der Rhenium(II)Thionitrosylkomplexe trans-[Re(NS)Cl3(MePh2P)2] und trans-[Re(NS)Br3(Me2PhP)2]

Preparation, Structures, and EPR Spectra of the Rhenium(II) Thionitrosyl Complexes trans -[Re(NS)Cl₃(MePh₂P)₂] and trans -[Re(NS)Br₃(Me₂PhP)₂] The paramagnetic rhenium(II) thionitrosyl compounds trans-[Re(NS)Cl₃(MePh₂P)₂] and trans-[Re(NS)Br₃(Me₂PhP)₂] are characterized by crystal structure diffraction and EPR spectroscopy. Trans-[Re(NS)Cl₃(MePh₂P)₂] is formed during the reduction of (a) [ReNCl₂(MePh₂P)₃] with disulphur dichloride or (b) of mer-[ReCl₃(MePh₂P)₃] with trithiazyl chloride. Trans-[Re(NS)Br₃(Me₂PhP)₂] is the final product of the ligand exchange reaction of mer-[Re(NS)Cl₂(Me₂PhP)₃] with bromine whereby the metal occurred to be simultaneusly oxidized. The crystal structure analyses show for trans-[Re(NS)Cl₃(MePh₂P)₂] (monoclinic, C2/c, a = 13.831(3) Å, b = 13.970(1) Å, c = 14.682(2) Å, β = 95.33(1), Z = 4) and trans-[Re(NS)Br₃(Me₂PhP)₂] (monoclinic, C2/c, a = 33.292(5) Å, b = 8.697(1) Å, c = 17.495(3) Å, β = 115.65(1), Z = 8) linear co-ordinated NS ligands (Re–N–S-angles 180° and 174.8°). The metal atom is octahedrally co-ordinated with the phosphine ligands in trans position to each other. X-band and Q-band EPR spectra of the rhenium(II) thionitrosyl complexes (5 d⁵ “low-spin” configuration, S = 1/2) are detected in the temperature range 295 ≥ T ≥ 130 K. They are characterized by well resolved ^185,187Re hyperfine patterns. The hyperfine parameters are used to get information about the spin-density distribution of the unpaired electron in the complexes under study.     

[ReCl2(NS)(NSCl)(Pyridin)2], ein Thionitrosyl-chlorthio-nitrenkomplex des Rheniums

[ReCl₂(NS)(NSCl)(Pyridine)₂], a Thionitrosyl-chlorothionitrene Complex of Rhenium The title compound was obtained by the reaction of pyridine with either [ReCl₃(NSCl)₂POCl₃] or [ReCl₃(NSCl)₂]₂ · (μ-N₂S₂) under the reducing action of dichloromethane. It is slightly soluble in CH₂Cl₂, from which it can be obtained in form of black crystals. The IR spectrum is reported. The crystal structure of [ReCl₂(NS)(NSCl)(Pyridine)₂] was determined by X-ray diffraction (R = 0.027 for 2105 observed reflexions). Crystal data: a = 1551.6, b = 694.9, c = 1513.2 pm, β = 96.50°, space group P2₁/c, Z = 4. In the monomer molecules, each rhenium atom has a distorted octahedral coordination of two cis-chlorine atoms, two cis-nitrogen atoms of the pyridine ligands and two cis-nitrogen atoms of the thionitrosyl and chloro thionitrene ligands. One of the pyridine groups is in trans position to the nearly linear thionitrosyl group (angle ReNS 176°) with distances ReN of 177 pm and NS of 152 pm. However, in the trans position of the chlorothionitrene group (angle ReNS 159°, distances ReN 189 pm, NS 149 pm) a chlorine atom is found.     

Thionitrosylkomplexe des Rutheniums. Die Kristallstruktur von (PPh4)2[{RuBr4(NS)}2(μ-N2S2)]

Thionitrosyl Complexes of Ruthenium. Crystal Structure of (PPh₄)₂[{RuBr₄(NS)}₂ (μ-N₂S₂)] Ruthenium trichloride reacts with trithiazyl chloride, yielding cis-RuCl₄ (NS)₂. With triphenylmethylphosphonium chloride this forms the complex [RuCl₄(NS)₂Cl]^? in which a chloride ion is bonded between the sulfur atoms in a chelate manner. With tetraphenylphosphonium bromide, RuCl₄(NS)₂ undergoes a redox reaction that affords (PPh₄)₂[{RuCl₄(NS)}₂(μ-N₂S₂)] which can be transformed to the title compound by the action of trimethylsilyl bromide. The i.r. spectra are reported. The crystal structure of (PPh₄)₂[{RuBr₄(NS)}₂(μ-N₂S₂)] · 4 CH₂X₂ (X ? Cl, Br) was determined with X-ray diffraction data (1534 observed reflexions, R = 0.085). Crystal data: monoclinic, space group P2₁/n, Z = 2, a = 1680.7, b = 1287.0, c = 1706.1 pm and β = 99.97°. The compound consists of tetraphenylphosphonium cations, CH₂Br₂ and CH₂Cl₂ molecules (statistically) and centrosymmetric anions [{RuBr₄(NS)}₂(μ-N₂S₂)]^2? in which the ruthenium atoms are linked via the nitrogen atoms of a planar N₂S₂ ring. In the corresponding trans-positions every Ru atom has a thionitrosyl ligand with a nearly arrangement Ru?N?S with RuN and NS bond lengths of 169 und 151 pm, respectively. Four bromine atoms complete the distorted octahedral coordination of each ruthenium atom. The bromine atoms that are coplanar with the N₂S₂ ring form rather short Br…?S contacts with a mean distance of 317 pm.     

Thermal decomposition of Pr[(C_5H_8NS_2)_3(C_(12)H_8N_2)]

The thermal behavior of the complex Pr[(C5H8NS2)3(C12H8N2)] in a dry nitrogen flow was examined by TG-DTG analysis. The TG-DTG investigations indicated that Pr[(C5H8NS2)3-(C12H8N2)] was decomposed into Pr2S3 and deposited carbon in one step where Pr2S3 predominated in the final products. The results of non-isothermal kinetic calculations showed that the decomposition stage was the random nucleation and subsequent growth mechanism (n = 2/3), the corresponding apparent activation energy ?was 115.89 kJ·mol-1 and the pre-expo-nential constant ln[A/s] was 7.8697. The empirical kinetics model equation was proposed as/(α) =3/2(1-α)[-ln(1-α)]1/3.The X-ray powder diffraction patterns of the thermal decomposition products at 800℃under N2 atmosphere show that the product can be indexed to the cubic Pr2S3 phase. The transmission electron microscopy (TEM) of the final product reveals the particle appearance of a diameter within 40 nm. The experimental results show that the praseodymium sulfide nanocrystal can be prepared from thermal decomposition of Pr[(C5H8NS2)3(C12H8N2)].     

Thionitrosylkomplexe des Osmiums. Die Kristallstruktur von AsPh4[OsCl4(NS)2Cl]

Thionitrosyl Complexes of Osmium. Crystal Structure of AsPh₄[OsCl₄(NS)₂Cl] The reaction of osmium pentachloride with trithiazyl chloride (NSCl)₃ yields the thiazylchloride complex [OsCl₄(NSCl)₂], from which the thionitrosyl complex AsPh₄[OsCl₄(NS)₂Cl] is obtained by reaction with AsPh₄Cl in CH₂Cl₂. From this, the neutral thionitrosyl complex [OsCl₄(NS)₂] forms by chloride abstraction with gallium trichloride. The crystal structure of AsPh₄[OsCl₄(NS)₂Cl] was determined and refined with the aid of X-ray diffraction data (R = 0.033, 2161 reflexions). It crystallizes in the monoclinic space group P2₁/c with four formula units per unit cell. The lattice constants are a = 1735, b = 1058, c = 1578 pm and β 95.64°. In the [OsCl₄(NS)₂Cl]^? ion the osmium is octahedrally coordinated by four Cl atoms and two NS groups in a cis arrangement. The NS groups are essentially linear with the bond lengths Os?N 184 pm and N?S 146 pm. Loosely attached to one of the S atoms there is a Cl atom (S? Cl distance 228 pm); in the crystal it statistically belongs to both S atoms with an occupation probability of one half, and it cannot be decided whether there is a dynamical fluctuation between the S atoms or a static positional disorder. However, according to the i.r. spectrum the dynamical model seems more probable.     

Gemischtligand-Komplexe des Rheniums. VI. Darstellung und Strukturen der Rhenium?Thionitrosyl-Komplexe mer-[Re(NS)Cl2(Me2PhP)3] · CH2Cl2 und trans-[Re(NS)Cl3(Me2PhP)2]

Mixed-ligand Complexes of Rhenium. VI. Synthesis and X-Ray Structures of the Rhenium Thionitrosyl Complexes mer-[Re(NS)Cl₂(Me₂PhP)₃] · CH₂Cl₂ and trans-[Re(NS)Cl₃(Me₂PhP)₂] mer-Dichlorotris(dimethylphenylphosphine)(thionitrosyl)rhenium(I), mer-[Re(NS)Cl₂(Me₂PhP)₃], and trans-Trichlorobis(dimethylphenylphosphine)(thionitrosyl)rhenium(II), trans-[Re(NS)Cl₃(Me₂PhP)₂], are formed during the reaction of rhenium(V) mixed-ligand complexes of the general formula [ReN(Cl)(Me₂PhP)₂(R₂tcb)] with disulphur dichloride (HR₂tcb = N-(N,N-dialkylthiocarbamoyl)benzamidine). The chelating ligands are substituted during the reaction. mer-[Re(NS)Cl₂(Me₂PhP)₃] crystallizes monoclinic in the space group P2₁/n. The dimensions of the unit cell are a = 8.854(2); b = 31.295(3); c = 11.981(3) Å; β = 108.14(1)°; Z = 4. A final R value of 0.033 was achieved on the basis of 5 387 reflections with I ≥ 3σ(I). The rhenium atom is coordinated in a distorted octahedral environment. The Me₂PhP ligands are arranged meridionally cis to the linear thionitrosyl group. trans-[Re(NS)Cl₃(Me₂PhP)₂] crystallizes in the monoclinic space group C2/c with an unit cell of the dimensions a = 33.320(9); b = 8.446(1); c = 17.28(5) Å; β = 116.09(1)°, Z = 8. The R value converged at 0.026 on the basis of 5 460 independent reflections. The metal is octahedrally coordinated with the phosphine ligands in trans position to each other. The angle Re? N? S is 175.7(3)°.     

Design,structure-based focusing and in silico screening of combinatorial library of peptidomimetic inhibitors of Dengue virus NS2B-NS3 protease

Abstract  

Serine protease activity of the NS3 protein of Dengue virus is an important target of antiviral agents that interfere with the viral polyprotein precursor processing catalyzed by the NS3 protease (NS3pro), which is important for the viral replication and maturation. Recent studies showed that substrate-based peptidomimetics carrying an electrophilic warhead inhibit the NS2B-NS3pro cofactor-protease complex with inhibition constants in the low micromolar concentration range when basic amino acid residues occupy P₁ and P₂ positions of the inhibitor, and an aldehyde warhead is attached to the P₁. We have used computer-assisted combinatorial techniques to design, focus using the NS2B-NS3pro receptor 3D structure, and in silico screen a virtual library of more than 9,200 peptidomimetic analogs targeted around the template inhibitor Bz-Nle-Lys-Arg-Arg-H (Bz—benzoyl) that are composed mainly of unusual amino acid residues in all positions P₁–P₄. The most promising virtual hits were analyzed in terms of computed enzyme-inhibitor interactions and Adsorption, Distribution, Metabolism and Excretion (ADME) related physico-chemical properties. Our study can direct the interest of medicinal chemists working on a next generation of antiviral chemotherapeutics against the Dengue Fever towards the explored subset of the chemical space that is predicted to contain peptide aldehydes with NS3pro inhibition potencies in nanomolar range which display ADME-related properties comparable to the training set inhibitors.     

Binding of low molecular weight inhibitors promotes large conformational changes in the dengue virus NS2B-NS3 protease: fold analysis by pseudocontact shifts

The two-component dengue virus NS2B-NS3 protease (DEN NS2B-NS3pro) is an established drug target, but inhibitor design is hampered by the lack of a crystal structure of the protease in its fully active form. In solution and without inhibitors, the functionally important C-terminal segment of the NS2B cofactor is dissociated from DEN NS3pro ("open state"), necessitating a large structural change to produce the "closed state" thought to underpin activity. We analyzed the fold of DEN NS2B-NS3pro in solution with and without bound inhibitor by nuclear magnetic resonance (NMR) spectroscopy. Multiple paramagnetic lanthanide tags were attached to different sites to generate pseudocontact shifts (PCS). In the face of severe spectral overlap and broadening of many signals by conformational exchange, methods for assignment of (15)N-HSQC cross-peaks included selective mutation, combinatorial isotope labeling, and comparison of experimental PCSs and PCSs back-calculated for a structural model of the closed conformation built by using the structure of the related West Nile virus (WNV) protease as a template. The PCSs show that, in the presence of a positively charged low-molecular weight inhibitor, the enzyme assumes a closed state that is very similar to the closed state previously observed for the WNV protease. Therefore, a model of the protease built on the closed conformation of the WNV protease is a better template for rational drug design than available crystal structures, at least for positively charged inhibitors. To assess the open state, we created a binding site for a Gd(3+) complex and measured paramagnetic relaxation enhancements. The results show that the specific open conformation displayed in the crystal of DEN NS2B-NS3pro is barely populated in solution. The techniques used open an avenue to the fold analysis of proteins that yield poor NMR spectra, as PCSs from multiple sites in combination with model building generate powerful information even from incompletely assigned (15)N-HSQC spectra.     

Theoretical investigation of the mechanisms of reaction of NCN with NO and NS

Quantum-chemical calculations were performed on the mechanisms of reaction of NCN with NO and NS. Possible mechanisms were classified according to four pathways yielding products in the following four possible groups: N2O/N2S + CN, N2 + NCO/NCS, N2 + CNO/CNS, and CNN + NO/NS, labeled in order from p1/p1s to p4/p4s. The local structures, transition structures, and potential-energy surfaces with respect to the reaction coordinates are calculated, and the barriers are compared. In the NCN + NO reaction, out of several adduct structures, only the nitroso adduct NCNNO lies lower in energy than the reactants, by 21.89 kcal/mol; that adduct undergoes rapid transformation into the products, in agreement with experimental observation. For the NS counterpart, both thionitroso NCNNS and thiazyl NCNSN adducts have energies much lower than those of the reactants, by 43 and 29 kcal/mol, respectively, and a five-membered-ring NCNNS (having an energy lower than those of the reactants by 36 kcal/mol) acts as a bridge in connecting these two adducts. The net energy barriers leading to product channels other than p4s are negative for the NS reaction, whereas those for the NO analogue are all positive. The channel leading to p1 (N2O + CN) has the lowest energy (3.81 kcal/mol), whereas the channels leading to p2 (N2 + NCO) and p2s (N2 + NCS) are the most exothermic (100.94 and 107.38 kcal/mol, respectively).     

Synthesis and resolution of diethyl (1S,2S)-1-amino-2-vinylcyclopropane-1-phosphonate for HCV NS3 protease inhibitors

We herein describe an efficient synthesis of optically active diethyl 1-amino-2-vinylcyclopropane-1-phosphonate (analogous to 1-amino-2-vinylcyclopropane-1-carboxylate). The racemic phosphonate diethyl ester was obtained from an imine derived from aminomethylphosphonate diester and trans-1,4-dibromo-2-butene. Crystallizations of the dibenzoyl-l-tartaric acid salt allowed for separation of enantiomers. The enantiomerically pure material was used to synthesize an extremely potent tripeptide phosphonate inhibitor of HCV NS3 protease. X-ray crystal structure of the inhibitor bound to the HCV NS3 protease confirmed the absolute stereochemistry of the title compound.     

Hollow Capsule NiCo2NS Prepared by Self-Sacrificing Template Method for High-Efficiency Bifunctional Catalyst and Its Application in Zn-Air Battery

Exploring the application of high-efficiency bifunctional oxygen catalysts to rechargeable zinc-air batteries has been a research hotspot in recent years. We succeeded in obtaining NiCo₂NS with a hollow capsule structure through the self-sacrificing template method, which has a larger specific surface area and can provide more active sites for electrocatalysis relative to his solid. The introduction of S can change the valence distribution of N and the electronic structure of the M−N bond, so that NiCo₂NS exhibits excellent performance in the overpotential and stability of the oxygen reduction and oxygen evolution reactions. It shows an overpotential of 154 mV at 10 mA cm⁻² and a half-wave potential of 0.76 V. When used as a bi-functional catalyst in zinc-air batteries, it exhibits good stability within 400 h. The flexible battery assembled by NiCo₂NS also shows excellent performance, and can be cycled stably for 20 h. The current maintains good stability when it is bent at different angles during the cycle.     

Insight into the structural requirements of narlaprevir-type inhibitors of NS3/NS4A protease based on HQSAR and molecular field analyses

In the life cycle of hepatitis C virus (HCV), NS3/NS4A protease has been proved to play a vital role in the replication of the HCV virus. Narlaprevir and its derivatives, the inhibitors of NS3/NS4A, would be potentially developed as important anti-HCV drugs in the future. In this study, quantitative structure-activity relationship (QSAR) analyses for 190 narlaprevir derivatives were conducted using comparative molecular field analysis (CoMFA), comparative molecular indices analysis (CoMSIA) and hologram quantitative structure-activity relationship (HQSAR) techniques. Both of the best CoMFA and HQSAR models showed statistical significance for the training set and good predictive accuracy for the test set, which strongly manifested the robustness of the CoMFA and HQSAR models. The CoMFA contour maps and the HQSAR contribution maps were both presented. Furthermore, based on the essential factors for ligand binding derived from the QSAR models, sixteen new derivatives were designed and some of them showed higher inhibitory activities confirmed by our models and molecular docking studies. General speaking, this study provides useful suggestions for the design of potential anti-HCV drugs.     

3D QSAR and molecular docking studies of benzimidazole derivatives as hepatitis C virus NS5B polymerase inhibitors

The urgent need for novel HCV antiviral agents has provided an impetus for understanding the structural requisites of NS5B polymerase inhibitors at the molecular level. Toward this objective, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of 67 HCV NS5B polymerase inhibitors were performed using two methods. First, ligand-based 3D QSAR studies were performed based on the lowest energy conformations employing the atom fit alignment method. Second, receptor-based 3D QSAR models were derived from the predicted binding conformations obtained by docking all NS5B inhibitors at the allosteric binding site of NS5B (PDB ID: 2dxs). Results generated from the ligand-based model were found superior (r2cv values of 0.630 for CoMFA and 0.668 for CoMSIA) to those obtained by the receptor-based model (r2cv values of 0.536 and 0.561 for CoMFA and CoMSIA, respectively). The predictive ability of the models was validated using a structurally diversified test set of 22 compounds that had not been included in a preliminary training set of 45 compounds. The predictive r2 values for the ligand-based CoMFA and CoMSIA models were 0.734 and 0.800, respectively, while the corresponding predictive r2 values for the receptor-based CoMFA and CoMSIA models were 0.538 and 0.639, respectively. The greater potency of the tryptophan derivatives over that of the tyrosine derivatives was interpreted based on CoMFA steric and electrostatic contour maps. The CoMSIA results revealed that for a NS5B inhibitor to have appreciable inhibitory activity it requires hydrogen bond donor and acceptor groups at the 5-position of the indole ring and an R substituent at the chiral carbon, respectively. Interpretation of the CoMFA and CoMSIA contour maps in context of the topology of the allosteric binding site of NS5B provided insight into NS5B-inhibitor interactions. Taken together, the present 3D QSAR models were found to accurately predict the HCV NS5B polymerase inhibitory activity of structurally diverse test set compounds and to yield reliable clues for further optimization of the benzimidazole derivatives in the data set.     

Chemiluminescence of NS radical produced by the reaction of active nitrogen with sulfur vapor and sulfur chloride

Kinetics of NS (B² Π → X²Π) emission produced by the reaction of active nitrogen with sulfur vapor or sulfur chloride (S₂Cl₂) has been studied as a function of the total pressure and of the concentrations of atomic nitrogen and sulfur. The B ²Π state of NS is selectively formed by the three-body recombination reaction of N ans S atoms, N(⁴S) + S(³P) + M →. NS(B ²Π) + M. The highest vibrational level of the B ²Π state observed is ν′ = 12, which gives a lower bound for the dissociation energy of 4.93 eV.     

Synthese und Kristallstruktur von Tetraphenylphosphonium-Aquabis(tetrasulfido)thionitrosyl-Osmat,PPh4[Os(NS)(S4)2(H2O)]

Synthesis and Crystal Structure of Tetraphenylphosphonium Aqua-bis(tetrasulfido)thionitrosyl Osmate, PPh₄[Os(NS)(S₄)₂(H₂O)] PPh₄[Os(NS)(S₄)₂(H₂O)] has been prepared as redbrown crystals by reacting PPh₄[OsNCl₄] with a solution of excess disodium tetrasulfide in dimethylformamide/H₂O and characterized by IR spectroscopy and by a crystal structure determination. Space group P2₁/n, Z = 4, structure solution with 4162 independent reflections, R = 0.059 for reflections with I > 2σ(I). Lattice dimensions at ?40°C: a = 1138.9(5), b = 1301.4(4), c = 2092.7(7) pm, β = 104.74(3)º. Os? N, Os? O, and Os? S distances are 175.2(12), 219.8(12), and 237.5(4)?239.1(4) pm, respectively. The Os?N?S moiety is approximately linear, with an OsNS angle of 171.2(7)º.     

Electrochemical detection of hepatitis C viral NS3-4A protease

Here we lay the ground work for the detection of hepatitis C viral NS3-4A protease exploiting peptide-protein interaction. The NS3-4A protease is inhibited by N-terminal cleavage products. Our approach is based on the formation of a self-assembled monolayer (SAM) of a ferrocene amino acid derivative on an electrode surface. A short NS3-4A specific inhibitory peptide (Asp-Glu-Ile-Val-Pro-Nva) was then covalently attached to the electrode surface. The interaction of the peptide, through the C-terminal, with the protein was quantified using electrochemical techniques. The systems exhibit a linear relationship between the measured signal and NS3-4A concentration in the range of 10-100 pM with a detection limit of 5 pM.     

Molecular modeling based approach to potent P2-P4 macrocyclic inhibitors of hepatitis C NS3/4A protease

Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.     

Discovery of Bispecific Lead Compounds from Azadirachta indica against ZIKA NS2B-NS3 Protease and NS5 RNA Dependent RNA Polymerase Using Molecular Simulations

Zika virus (ZIKV) has been characterized as one of many potential pathogens and placed under future epidemic outbreaks by the WHO. However, a lack of potential therapeutics can result in an uncontrolled pandemic as with other human pandemic viruses. Therefore, prioritized effective therapeutics development has been recommended against ZIKV. In this context, the present study adopted a strategy to explore the lead compounds from Azadirachta indica against ZIKV via concurrent inhibition of the NS2B-NS3 protease (ZIKV^pro) and NS5 RNA dependent RNA polymerase (ZIKV^RdRp) proteins using molecular simulations. Initially, structure-based virtual screening of 44 bioflavonoids reported in Azadirachta indica against the crystal structures of targeted ZIKV proteins resulted in the identification of the top four common bioflavonoids, viz. Rutin, Nicotiflorin, Isoquercitrin, and Hyperoside. These compounds showed substantial docking energy (−7.9 to −11.01 kcal/mol) and intermolecular interactions with essential residues of ZIKV^pro (B:His⁵¹, B:Asp⁷⁵, and B:Ser¹³⁵) and ZIKV^RdRp (Asp⁵⁴⁰, Ile⁷⁹⁹, and Asp⁶⁶⁵) by comparison to the reference compounds, O7N inhibitor (ZIKV^pro) and Sofosbuvir inhibitor (ZIKV^RdRp). Besides, long interval molecular dynamics simulation (500 ns) on the selected docked poses reveals stability of the respective docked poses contributed by intermolecular hydrogen bonds and hydrophobic interactions. The predicted complex stability was further supported by calculated end-point binding free energy using molecular mechanics generalized born surface area (MM/GBSA) method. Consequently, the identified common bioflavonoids are recommended as promising therapeutic inhibitors of ZIKV^pro and ZIKV^RdRp against ZIKV for further experimental assessment.